Molecular cloning of the human type II IGF receptor by Rutter and his collaborators revealed an 80% sequence homology with the bovine cation independent mannose 6-phosphate receptor suggesting that this receptor is multifunctional, binding both IGF-II and lysosomal enzymes. We have performed biochemical experiments which support this proposal. Rat liver type II IGF receptor, purified by the conventional method of IGF-II affinity chromatography, bound quantitatively to a B-galactosidase affinity column and was eluted with Man-6-P. Bovine liver Man-6-P receptor prepared using the conventional method of affinity chromatography on phosphomannan Sepharose, bound IGF-II with high affinity (Kd=lnM). For immunologic studies, we purified type II IGF receptors and Man-6P receptors in parallel from rat placental membranes using either IGF-II-or B-galactosidase affinity chromatography. A panel of 5 antisera that previously had been raised against either type II IGF receptor or Man-6-P receptor, behaved identically toward type II receptor versus Man-6-P receptor in ligand blocking and immunoprecipitation assays. We have performed additional experiments to define interactions of the two classes of ligands (IGFs and lysosomal enzymes) for binding to the IGF-II/Man-6-P receptor. We found that a panel of lysosomal enzymes inhibited the binding of 125-IGF-II to the purified receptor and that this inhibition resulted from a change in the binding affinity for IGF-II. We also examined the ability of IGF-II to modulate the binding of radiolabeled lysosomal enzyme (B-galactosidase) to the receptor. IGF-II inhibited the binding of 125 I-B-galactosidase to purified receptor and also inhibited the uptake of 125 B galactosidase in two cell lines in culture (C6 and BRL-3A) via the IGF-II/Man-6-P receptor. Additionally, we have examined the developmental pattern of IGF-II/Man-6P receptor expression by extracting rat tissues and performing Western blotting using an antisera which is highly specific for the IGF-II/Man-6-P receptor. We found that the receptor is present in multiple tissues at levels as high as 1% of extractable protein and that the receptor is developmentally regulated, being high in fetal tissues and declining postnatally to much lower level by day 20.